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Person-to-person transmission of CJD was first recognized in 1973 in a patient who 18 months earlier had received a corneal graft from a donor who was only belatedly discovered to have died of CJD. Stereotactic EEG electrodes were implicated in two cases of CJD a few years later, and retrospective studies have identified a handful of cases that most probably resulted from inadequately sterilized neurosurgical instruments. Apart from two possible further cases of CJD from corneal grafts, all other known cases of iatrogenic CJD have been caused by contaminated pituitary hormones, or contaminated grafts of dura mater (the protective membrane that surrounds the brain). The current world-wide tally of iatrogenic CJD from all causes is approximately 250 cases.
The clinical features of iatrogenic disease appear to depend upon the route of infection. Intracerebral infections (neurosurgery and corneal grafts via the optic nerve) have incubation periods of about one and a half years and a clinical presentation similar to sporadic CJD; cerebral surface infections (dura mater grafts) have incubation periods ranging from one and a half to 18 years (average, 6 years) and diverse clinical presentations; and peripheral route infections (pituitary hormones) have an even wider range of incubation periods (average, 12 years), with prominent incoordination and a course of illness marked by little if any mental deterioration.
Environmentally-acquired cases of CJD are either ‘iatrogenic’ (meaning that they are unknowingly caused by physicians), or more recently, infectious due to the consumption of contaminated beef from cattle with BSE. Fortunately, the number of such cases remains comparatively small, and measures have been taken to prevent future infections. Nevertheless, because we did not immediately appreciate the causes of these acquired infections, and because the period of time elapsing between infection and illness can be so long, new cases of CJD continue to occur after longer and longer incubation periods from infections acquired during the 1970s and 1980’s.
The other source of environmentally acquired CJD, now called ‘variant CJD’ (vCJD) first appeared in 1994 and has since been occurring at a more or less steady rate of about 10-20 new cases per year. As of January 2001 it had been responsible for 93 cases in the United Kingdom, three cases in France, and one case in the Republic of Ireland. Strictly speaking, its only association with BSE is that both diseases are largely confined to Great Britain. However, epidemiologic, biologic, and molecular biologic evidence has converged to implicate infection by BSE as the cause of vCJD, and a consideration of slaughtering practices has revealed numerous ways by which beef could have become contaminated with tissue from the central nervous system.
Clinically, the most striking feature of vCJD is the youthfulness of its victims, who range in age from 14 to 52 years (average, 28 years), and thus clearly separate from the major 55-75 year age bracket of sporadic disease. The clinical presentation seen in most patients consists of psychiatric or sensory symptoms, rather than the usual mental-cerebellar-visual onset of sporadic disease. The illness progresses at a comparatively leisurely pace, with an average duration of 14 months, and no case dying in less than 7 months. Eventually, most of the features of sporadic disease appear, including dementia and myoclonus, but no case has shown a periodic EEG. Because each of these features has also occurred in cases of sporadic CJD, a definitive diagnosis of vCJD can only be established at autopsy by the unique microscopic finding of plaques surrounded by petals of spongiosis (‘daisy’ plaques).
Predictions about the future extent of the outbreak remain shrouded in uncertainty, and mathematical modeling has produced estimates from a few hundred to more than a hundred thousand cases, almost all of which would be in residents of Great Britain. However, BSE has occurred in much lower incidence in other European countries as a result of imported livestock protein supplements made from the rendered carcasses of British cattle, and potentially contaminated British beef continued to be exported to other (mainly European) countries during the 1980’s when the BSE epidemic was evolving. The fact that three cases of vCJD have occurred in French citizens who had never visited Britain signals the probability that at least a few cases will occur in other European countries, and perhaps also in long-term visitors to Great Britain. The implications of this for iatrogenic transmission of CJD as a result of incubating infections in apparently healthy people who are undergoing surgery, donating blood, or being used as sources of organ transplants, continue to create enormous concern among physicians, scientists, governments, and the general public.
Two approaches are possible for environmentally-acquired disease: eliminate the sources of infection, and block the routes of invasion from the periphery of the body to the brain. As noted, the sources of both iatrogenic and BSE infections have to the best of our knowledge been either eliminated or reduced to a level that is too low to be detected. Erecting barricades to the passage of the infectious agent to the brain has recently shown some promise in experimental models, but remains imperfect and far from being ready for human clinical trials. The major problem is that infectivity in these models can be tracked along at least two, and possibly three different routes to the brain: one route passes through the spleen and spinal cord, one route passes directly to the brain via nerves, and a possible third route reaches the brain via the bloodstream. In consequence, any effective therapy is going to have to be capable of blocking all three routes, and will almost certainly require more than one blocking strategy and more than one drug.
Work is going on in several laboratories to develop a screening test to identify infected individuals before their symptoms begin. If such a test can be developed, its application in combination with early preventive drug therapy may finally spell an end to these rare but ravaging diseases